Pharmaceutical intermediates



Patented Feb. 27, 1951 2,543,187 7 PHARMACEUTICAL INTERMEDIATES Edmond E. Moore and Marjorie B. Moore, Waukegan, I1l., assignors to Abbott Laboratories, North Chicago, 111., a corporation of Illinois No Drawing. Original application April 7, 1943,

Serial No. 482,205.

Divided and this application February 13, 1947, Serial No. 728,377

1 Claim. 1

This application is a division of our copending application, Ser. No. 482,205, filed April 7, 1943, now abandoned.

The present invention relates to products of interest in the therapeutic field and improved processes of preparing the same. More specifically, the present invention is directed to the synthesis of valuable intermediates having particu" lar utility in the preparation of certain vitamins or vitamin-like substances.

The principal object of the present invention is to provide products for use in the preparation of therapeutically active compounds including compounds used in vitamin therapy.

Another object of the present invention is to provide improved processes of preparing products for use in the preparation of therapeutically active compounds.

Other objects of the present invention will be apparent from the detailed description hereinafter.

Included among the intermediates of the present invention are the di-lower alkyl esters of ,B-(carboxymethylthio) propionic acid. The diethyl ester derivative of the [3-(carboxymethylthio) propionic acid may be represented by the following formula:

01120 O O CzHs These products may be prepared by the following improved methods:

(a) By reacting thioglycollic acid with a lower alkyl acrylate in the presence of an organic base such as pyridine, removing the organic base and esterifying the free carboxyl group by use of the appropriate alcohol and acid. The following equations illustrate this preparation:

reanic HSCHQCOOH CHg -CHCOOR T CHzCOOH CHzCOOR CHzCHzCO O R The I 2 fl-(carboxymethylthio) propionitrile to the diester by heating with the appropriate alcohol and acid, hydrolyzing and esterifying mixture. The following equations illustrate this preparation:

Organic HSCHZCOOH OH2=CHCN base CHZCOOH CH2COOR Mineral S ROH S acid CHzCHzCN OHiOHzCOOR EXAMPLE 1' a. Mono-ethyl ester of p-(carboxymeth'ylthio) propiom'c acid A mixture made up of about 22 grams of thioglycollic acid, 45 grams of ethylacrylate and 0.5 gram of pyridine is first heated in a closed vessel at about C. for about eight hours. The excess ethylacrylate along with the pyridine are next removed by distillation.

b. Di-ethyl ester of 3-(cdrbethomymethfllthio propz'om'c acid The crude half ester product obtained as in a above is converted into the diester by saturating an absolute alcohol solution of the half ester with hydrogen chloride gas. After the reaction is complete the acid is neutralized with alkali (e. g. NaOH) and the crude product purified by fractional distillation under reduced pressure. The desired product boils at about 136-138 C. at 8 mm. pressure.

EXAMPLE 2 a. c(c'arboarymethylthio) propio'nitrile About 21 grams of thioglycollic acid and about 24 grams of acrylonitrile mixed with about 0.5 gram of pyridine are first heated for about eight hours at 100 C. in a closed vessel. The excess 'acrylonitrile andpyridine are next'removed by distillation in accordance with standard practices.

The crude product obtained as in a above is hydrolyzed and esterified as follows: A mixture made up of about 14.5 grams of B-(carboxymethylthio) propionitrile, 20 cc. of concentrated sulfuric acid and 47.6 cc. of ethyl alcohol (95%) is refluxed for about seven hours and allowed to stand over night. The reaction mixture is next diluted with about cc. of ethyl alcohol to precipitate ammonium sulfate, the resulting solution concentrated to about 60 cc. and then poured in about 400 cc. of water. The aqueous mixture is next extracted with ether, the ether extract washed with a solution of sodium carbonate, then with water and finally dried over anhydrous sodium sulfate, in accordance with standard practices. The solvent is then recovered and the crude material distilled as in Example 1.

EXAMPLE 3 B-(C'arbethoxymethylthz'o) propionitrile A mixture made up of about 24 grams of ethyl thioglycolate, 21.5 grams of acrylonitrile and 0.5 gram of pyridine is heated at about 100 C. for about eight hours in a closed vessel. The excess acrylonitrile is recovered by distillation and the residue fractionally distilled. The desired product which boils at about 120-125 C. at 3 mm. pressure, may be hydrolyzed and converted into the di-lower alkyl ester by use of the appropriate alcohol in accordance with the general process outlined in b of Example 2.

The intermediates of the present invention also include the diesters of derivatives of the above compounds where, for example, one of the hydrogen atoms on the alpha carbon atom of the propionic radical has been replaced by an amino group. The dimethyl ester derivative of this ,6-

(carboxymethylthio) a aminopropionic acid compound may be represented by the following formula:

CH2COOCH2 CH2CHCOOCHa These products, which may be prepared by esterifying the free carboxyl groups as outlined above, react with acyl halide compounds such as benzoyl chloride to form intermediates of particular value in the synthesis of therapeutic products. The preparation of these intermediates may be illustrated by the following equations:

where R is a lower alkyl group and A represents an aryl radical such as phenyl, naphthyl, etc., an alkyl radical such as propyl, butyl, etc. or an aralkyl radical such as benzyl, etc. In the preparation of these products as shown above B-(carboxymethylthio) a-aminopropionic acid is first reacted with the desired acid (ACO) halide in the presence of alkali. After acidification the reaction mixture is extracted with a water immiscible solvent, the solvent removed by evaporation, the residue taken up in dry alcohol and esterified in the usual manner. The acidic esterification reaction mixture is next neutralized and the solvent alcohol and esters removed by distillation under reduced pressure at a temperature below that at which decomposition of the desired diester product takes place. The following example will serve to illustrate this process.

EXAMPLE 4 Ethyl ester of 5-(carbethorymethg Zthio) a-N- benzoylaminopropionic acid To an aqueous solution containing about one mol of ,B-(carboxymethylthio) a-aminopropionic acid is added about five molar proportions of sodium hydroxide. The solution is next cooled and about 1.5 molar proportions of benzoyl chloride added with stirring, the stirring being continued until the odor of the acid chloride has disappeared. The reaction mixture is also warmed near the end of the reaction to assure its completion. About 5.5 molar proportions of concentrated hydrochloric acid are next added to the reaction mixture to precipitate the solid fi-(carboxymethylthio) a N benzoylaminopropionic acid, together with some benzoic acid formed in the reaction. The crude product obtained is dried and then esterified by suspending in absolute alcohol and passing in dry hydrogen chloride while cooling in an ice-bath. After saturation, the reaction mixture is preferably allowed to stand at room temperature for about twenty-four hours in a closed (stoppered) vessel. The alcohol and HCl are next removed by vacuum distillation, the residue taken up in ether, the ether solution Washed with aqueous sodium carbonate to remove acidic material, and the ether solution dried over anhydrous sodium sulfate. The other is then evaporated and the residue freed from ethyl benzoate and other volatile impurities by distilling,

at about 5 mm. pressure at a bath temperature below C. The liquid residue remaining con-. tains the desired ester and While it cannot be distilled without decomposition, it is suitable in its crude form for use in the cyclization to the [iketo ester described hereinafter. The product obtained by this process may be illustrated by the following formula:

CHzC O O Cz s In the above reactions the use of an aromatic acyl halide is preferred. Aliphatic acid halides (e. g. acetyl chloride, butyryl bromide, etc), however, may be used although such reactions are usually complicated by the formation of unwanted azlactones.

The ,B-(carbalkoxymethylthio) propionic acid esters or the a acyl amino derivatives described above, may be condensed to form carbalkoxy-S- oxo-tetrahydrothiophenes. The cyclization or intramolecular condensation may be carried out in the presence of sodium ethylate, sodium tri- 5 6 r phenyl methyl, etc., and may be illustrated by the thio) a-N-benzoylaminopropionate, represented following equation: by the following formula:

COOR CHzCOOCzHs CHzC 0 R Alkali CHC=O S metal S S CHzCHCOOO H condensation CHMFHCOOR agent CH2-(|JH NH X X (1:0 where the Rs represent lower alkyl groups, and 10 H5 X is H or NHCOR", where R" is alkyl or aryl or EDMOND E. MOORE aralkyl- MARJORIE B. MOORE.

The tetrahydrothiophene compounds are of particular value for use in the synthesis of phar- REFERENCES CITED maceutically active compounds such as vitamins and the like. They are described in detail in our g ig fi fi are of record m the co-pending application, Serial No. 482,206, now p Patent No.2,472,433. UNITED STATES PATENTS It will be understood that the present inven- Number Name Date tion is not limited to the above illustrative ex- 2,163176 Keyssner June 20 1939 amples. All modifications Of the present inven- 2,322,273 Biggs June 22, 1943 tion are intended to be covered b the claim annexed herem y OTHER REFERENCES We claim: Journal of Biological Chemistry, vol. 139 (1941) The compound, ethyl-B- (carbethoxymethylpp. 407-412, 6 pp. 

